SAN DIEGO, Oct. 22 /PRNewswire/ — OREXIGEN™ Therapeutics, Inc., a
privately held clinical-stage neuroscience company developing novel
strategic approaches to the treatment of obesity, today announced that
Excalia™, a combination of two centrally-acting medications intended to
provide and sustain clinically important weight loss, demonstrated
significant weight loss in a six month, double-blind, phase IIa clinical
study. The magnitude of weight reduction exceeded that seen with placebo.
The findings showed that patients completing the blinded 24-week phase lost
on average 9.2% of their weight from baseline using Excalia compared to an
average of 0.4% weight loss from baseline for patients using placebo. The
study results further demonstrate that weight loss continued through an
additional 24 week open- label period achieving an average weight loss of
12% from baseline by 48 weeks. These top line phase IIa data for Excalia
were presented at the annual meeting of the North American Association for
the Study of Obesity (NAASO) in Boston.

“Excalia is designed to achieve an aggressive weight loss trajectory
and then to delay the typical weight loss ‘plateau’ by offsetting one of
the body’s natural compensatory pathways. These phase II data suggest a
level of efficacy that exceeded our expectations in relation to existing
approaches,” said Gary Tollefson, M.D., Ph.D., OREXIGEN president and CEO.
“Excalia is designed to act on a specific reciprocally paired group of
hypothalamic neurons that we believe will yield a clinically meaningful
weight loss trajectory among significantly overweight individuals. We
believe that these positive data support our theoretical approach.”

Excalia is a proprietary combination of bupropion, a dopamine and
norepinephrine reuptake inhibitor, plus zonisamide, an approved
anticonvulsant medication. OREXIGEN’s preclinical research suggests that
combining these two central nervous system drugs acts on a complex of
neurons in the hypothalamus, the area of the brain contributing to the
regulation of appetite, energy output and maintaining body weight. The
compound was tested in a double-blind, placebo-controlled, randomized,
proof-of-concept phase II clinical study of 127 non-smokers with body mass
indices (BMI’s) between 30 and 40. At the end of the primary treatment
interval Excalia was associated with advantages over both the individual
components and placebo (see table below). Study completers had lost in
excess of 9% of their baseline body weight by week 24.

Excalia Zonisamide + Bupropion + Placebo

Placebo Placebo

Completer -9.2 -6.6 -3.4 -0.4

Analysis

(p value) (p=0.025) (p=0.00003) (p<0.00001)

On categorical measures of response nearly three quarters (73%) of
those who completed the study demonstrated a 5% weight loss, and half (50%)
demonstrated a 10% weight loss at 24 weeks. After 24 weeks patients were
re- randomized for the extension phase of the study. Those staying on their
same dose of active therapy lost, [on average], an additional 3% from the
start of the study. Approximately one-third of subjects discontinued early
due to an adverse event consistent with the existing package insert for
zonisamide. In light of this rate, the company has implemented a strategy
that it believes will result in improved tolerability in current and
forthcoming trials for Excalia.

36 Week Data for Contrave™

Separately, the company reported that the first cohort of patients
testing its other obesity compound, Contrave, continued to lose weight
without an indication of the common diet “plateau” as they reached the 36
week mark of a phase III, multi-center clinical trial. Contrave is a
combination of naltrexone and bupropion intended to provide a steady,
sustained weight loss trajectory with a mechanism of action differing from
Excalia. Contrave was rationally designed to block the compensatory effect
of beta-endorphin, a key component of the POMC pathway, a central nervous
system pathway that stimulates energy expenditure and reduces hunger.
Beta-endorphin has been reported to limit POMC and in turn, weight loss. In
September, OREXIGEN reported positive 24-week results for Contrave
(http://www.orexigen.com/news). The company believes that the new nine month data
further validate the scientific hypothesis underlying the development of
Contrave.

ABOUT OREXIGEN THERAPEUTICS

OREXIGEN™ Therapeutics, Inc. is a privately-held clinical-stage
neuroscience company in San Diego, California developing novel strategic
approaches to the treatment of obesity. OREXIGEN leverages its proprietary
science to design and screen two-drug combinations that work together in
the central nervous system to enhance satiety, diminish appetite, improve
energy expenditure and minimize the body’s efforts to compensate for weight
loss. OREXIGEN has two lead compounds in clinical trials, Contrave™
(phase III) and Excalia™ (phase IIb), along with a pipeline of earlier
stage drug combinations now being tested. Each is designed to act on a
specific group of neurons in the central nervous system with the goal of
achieving appetite suppression and sustained weight loss. By targeting
different groups of neurons OREXIGEN is working to develop compounds that
each can achieve a different weight loss profile, providing rapid weight
loss where required (Excalia) or emphasizing steady, sustainable weight
loss where preferred (Contrave). Further information about the company can
be found at http://www.orexigen.com.

OREXIGEN cautions you that statements included in this press release
that are not a description of historical facts are forward-looking
statements. These forward-looking statements include statements regarding
the efficacy and safety of Contrave™ and the potential to obtain
regulatory approval for, and effectively treat obesity with, any of
OREXIGEN’s product candidates. The inclusion of forward-looking statements
should not be regarded as a representation by OREXIGEN that any of its
plans will be achieved. Actual results may differ materially from those set
forth in this release due to the risks and uncertainties inherent in
OREXIGEN’s business, including, without limitation: the progress and timing
of OREXIGEN’s clinical trials, including the potential to replicate in
pending and future trials the results described in this press release for
Contrave™; the potential for Contrave™ to receive regulatory approval
on a timely basis or at all; the market potential for obesity, and
OREXIGEN’s ability to compete in the obesity market; and the scope and
validity of patent protection for OREXIGEN’s product candidates. You are
cautioned not to place undue reliance on these forward-looking statements,
which speak only as of the date hereof. All forward-looking statements are
qualified in their entirety by this cautionary statement and OREXIGEN
undertakes no obligation to revise or update this news release to reflect
events or circumstances after the date hereof.